Ketone homologation via palladium

Abstract
The decarboxylative semi-pinacol rearrangement of β-hydroxy carboxylic acids under electrochemical oxidation conditions was first reported in 19601. However, its further development has remained limited owing to stepwise radical and carbocationic pathways that induce side reactions and result in the loss of stereochemical information at the α-carbon. Herein, we demonstrate that this transformation can instead be realized through a concerted mechanism under Pd(II)/Pd(IV) catalysis. The reaction proceeds via the formation of a six-membered Pd(IV) chelate, which undergoes fragmentation accompanied by β-to-α carbon migration and carbon dioxide extrusion, with Pd(IV) serving as the redox center. This closed-shell pathway enables precise stereochemical control: the migrating carbon retains its absolute configuration, while the α-stereocenter undergoes inversion. For unsymmetrical ketones, the reaction displays markedly higher migrating-group selectivity than the classical Tiffeneau–Demjanov2 and Büchner–Curtius–Schlotterbeck reactions3. Broadly applicable to cyclic and acyclic ketones and aldehydes, this method avoids hazardous diazo reagents. Its utility is illustrated by a concise total synthesis of (+)-rupestine D, where the rearrangement serves as a key carbon-skeleton-editing step.
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Materials and Methods, containing the following sections: 1. General information; 2. Preparation of substrates; 3. Optimization of reaction conditions for palladium catalyzed decarboxylative ring-expansion process; 4. Representative procedures of the palladium catalyzed decarboxylative 1,2-rearrangement process; 5. Preparation and key reactions of 1bc, (2R*, 3R*)-1bc and (2S*, 3R*)-1bc; 6. Hammett plots for a series of para-substituted aryl β-carboxylic acids; 7. Migratory selectivity study and one carbon ring expansion of natural ketone derivatives; 8. Iterative homologation of cyclobutanone; 9. Total synthesis of natural product; 10. Crystallographic data; 11. Copies of NMR Spectra; and 12. References.
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Gong, J., Wang, Q. & Zhu, J. Ketone homologation via palladium-catalysed decarboxylative rearrangement. Nature (2026). https://doi.org/10.1038/s41586-026-11091-5
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DOI: https://doi.org/10.1038/s41586-026-11091-5

* The decarboxylative semi-pinacol rearrangement of $\beta$-hydroxy carboxylic acids was first reported in 1960.
* Previous methods involved stepwise radical and carbocationic pathways causing side reactions and loss of stereochemical information at the $\alpha$-carbon.
* The new method uses $\text{Pd}(\text{II})/\text{Pd}(\text{IV})$ catalysis for this transformation.
* The reaction proceeds via the formation of a six-membered $\text{Pd}(\text{IV})$ chelate.
* Fragmentation involves $\beta$-to-$\alpha$ carbon migration and carbon dioxide extrusion.
* $\text{Pd}(\text{IV})$ serves as the redox center in this closed-shell pathway.
* The migrating carbon retains its absolute configuration.
* The $\alpha$-stereocenter undergoes inversion during the rearrangement.
* For unsymmetrical ketones, the reaction shows higher migrating-group selectivity than classical reactions.
* The method is broadly applicable to cyclic and acyclic ketones and aldehydes.
* A total synthesis of (+)-rupestine D illustrated the utility of this rearrangement.

The decarboxylative semi-pinacol rearrangement of $\beta$-hydroxy carboxylic acids was previously reported in 1960, but previous methods suffered from stepwise radical and carbocationic pathways that led to side reactions and loss of stereochemical information at the $\alpha$-carbon. A new method utilizing $\text{Pd}(\text{II})/\text{Pd}(\text{IV})$ catalysis demonstrates a concerted mechanism for this transformation. This reaction proceeds through the formation of a six-membered $\text{Pd}(\text{IV})$ chelate, which fragments via $\beta$-to-$\alpha$ carbon migration and carbon dioxide extrusion, with the $\text{Pd}(\text{IV})$ species acting as the redox center. This closed-shell pathway allows for precise stereochemical control: the migrating carbon retains its absolute configuration while the $\alpha$-stereocenter undergoes inversion. For unsymmetrical ketones, this method shows superior selectivity compared to classical reactions like Tiffeneau–Demjanov and Büchner–Curtius–Schlotterbeck reactions. The method is applicable to cyclic and acyclic ketones and aldehydes and avoids hazardous diazo reagents, as demonstrated in the total synthesis of (+)-rupestine D.

The shift from stepwise radical/carbocationic mechanisms to a concerted $\text{Pd}(\text{II})/\text{Pd}(\text{IV})$ pathway represents a fundamental advancement in synthetic chemistry, moving from non-selective transformations to highly stereocontrolled bond formations. The core implication is the ability to control molecular architecture at the $\alpha$-center via predictable migratory steps and inversion, bypassing the inherent loss of stereochemical information common in older methods. This mechanistic control suggests that transition metal catalysis can enforce specific conformational outcomes, suggesting that reaction pathways are not merely kinetic outcomes but are dictated by accessible, low-energy orbital interactions within a defined transition state geometry—the six-membered chelate provides this necessary constraint. The improved migratory selectivity observed with unsymmetrical ketones further establishes the power of tuning the metal oxidation state to direct regioselectivity. The method’s utility in avoiding diazo reagents for synthesizing complex structures like (+)-rupestine D highlights a practical bridge between theoretical mechanistic elegance and practical synthetic feasibility, suggesting that highly selective, safer catalytic routes can be superior tools for constructing complex carbon skeletons with defined chirality. What is the next logical step in applying this principle to complex polyfunctional systems where multiple stereocenters are present simultaneously?

Ketone homologation via palladium

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Ketone homologation via palladium

Facts Only

Executive Summary

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Sentinel — Human